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The purpose of this study is to determine if prazosin is more effective than placebo in decreasing frequency, severity, disability, and other negative effects of headaches related to mild traumatic brain injury in Service Members and Veterans.

Headaches following combat-related post-concussive injury are common, and in some patients can increase in frequency and severity to become very debilitating. Posttraumatic headaches (PTHAs), particularly those following blast-related head injury, can be resistant to standard headache therapies. The objective of this study is to evaluate the effectiveness of the medication prazosin as a prophylactic (preventive) agent in treating combat-related PTHAs. Prazosin is a generic drug originally marketed over 30 years ago as a treatment for high blood pressure. It has subsequently been found to be safe and effective for treating other problems, including most recently posttraumatic stress disorder (PTSD) and disrupted sleep in active duty Iraq/Afghanistan Service Members and Veterans. In preliminary studies, prazosin has also been found to substantially reduce the intensity and frequency of PTHAs in this population. This finding is the motivation behind this study.

The investigators' hypotheses are (1) that prazosin will be more effective than placebo in easing the effects of chronic PTHAs, including headache frequency, duration, severity, use of abortive/analgesic medications, and disability caused, and (2) that improvement in headache parameters will be associated with improvement in sleep quality, PTSD symptom severity, mood, cognition, health-related quality of life, and global clinical status, and with moderation of alcohol consumption.

The total trial length is 22 - 24 weeks. Following an initial clinic visit to determine preliminary study eligibility, there will be a 4-week pre-treatment preliminary screening period, during which participants will keep a daily headache diary. The purpose of this is to confirm eligibility for randomization per inclusion/exclusion criteria and to collect baseline data for headache-related outcome measures. Participants confirmed to be eligible to continue in the study will then have a one-week sleep evaluation including actigraphy and keeping a daily sleep diary. This will be followed by a baseline study visit, during which baseline data for secondary outcome measures will be collected using validated structured self-reports and clinician interviews. Participants will be randomized 2:1 to prazosin or placebo, and the study drug dose will be gradually titrated over a 5 to 7-week period to 5 mg in the morning and 20 mg in the evening or the maximum tolerated dose. The dose titration will be followed by 12 weeks at steady-dose. For the last week of the steady-dose phase, participants will repeat the sleep evaluation. Participants will keep a headache log through the duration of the study. Results will be analyzed using standard statistical techniques.

Subjects will be gradually titrated up to the maximum dose or the maximum tolerated dose based on a dosing algorithm. The maximum dose to be used in this trial is 5mg in the morning and 20 mg at bedtime.

Drug: prazosin hydrochloride

Prazosin as oral capsules titrated to the maximum dose or the maximum tolerated dose based on a dosing algorithm. The maximum dose to be used in this trial is 5mg in the morning and 20 mg at bedtime.

Other Name: Minipress

Placebo Comparator: placebo

Subjects will be gradually titrated up to the maximum dose or the maximum tolerated dose based on a dosing algorithm. The maximum dose to be used in this trial is 5mg in the morning and 20 mg at bedtime.

Drug: placebo

Oral capsules of placebo identical in appearance to prazosin capsules titrated in the same manner as prazosin.

Change from baseline (pre-treatment) to Week 12 (i.e., following 12 weeks of drug treatment) in average 4-week frequency of either 1) HAs that last 4 or more hours a day and reach a moderate to severe intensity at any point or 2) HAs of any intensity if a medication is taken in an effort to stop the HA, as determined from Headache Log data.

Change from baseline (pre-treatment) to Week 12 (i.e., following 12 weeks of drug treatment) in 4-week average peak HA severity, as determined from Headache Log data.

Change from Baseline in 4-week Average Total Number of Hours of HA Pain [ Time Frame: Baseline to 12 weeks ]

Change from baseline (pre-treatment) to Week 12 (i.e., following 12 weeks of drug treatment) in 4-week average total number of hours of HA pain of any severity, as determined from Headache Log data.

Change from Baseline in Frequency of Use of Abortive/Analgesic Agents [ Time Frame: Baseline to 12 weeks ]

Change from baseline (pre-treatment) to Week 12 (i.e., following 12 weeks of drug treatment) in 4-week average frequency of use of abortive and/or analgesic HA treatment medications, as determined from Headache Log data.

Change from baseline (pre-treatment) in average headache-related disability, as measured 1) in 4-week treatment intervals using the Headache Impact Test-6 and 2) in the full 12-week treatment interval using the Migraine Disability Assessment (for subjects who meet diagnostic criteria for migraine).

Change from baseline (pre-treatment) in PTSD symptom severity, as measured 1) using the Clinician-Administered PTSD Scale for DSM-V given at baseline and after 12 weeks of treatment and 2) using the PTSD Checklist (PCL) given at baseline and at 4-week treatment intervals.

Change from baseline (pretreatment) in sleep characteristics, including sleep quality, quantity, and efficiency using 1) the Pittsburgh Sleep Quality Index and the Insomnia Severity Index given at baseline and at 4-week treatment intervals and 2) sleep diary and wrist actigraphy performed for one week at baseline and after 11 weeks of treatment

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Ages Eligible for Study:

18 Years and older (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Veterans or active duty service members aged 18 or older of either gender

Good general health

History of blast and/or impact head/neck trauma meeting DVBIC criteria for mild TBI, i.e., injury as manifested by at least one of the following:

1) any period of loss of consciousness

2) any loss of memory for events immediately before or after the accident

3) any alteration in mental status at the time of the accident (e.g., feeling dazed, disoriented, or confused)

4) focal neurological deficit(s) that may or may not be transient, with severity of injury not exceeding loss of consciousness 30 minutes, Glasgow Coma Scale <13-15 after 30 minutes, or posttraumatic amnesia >24 hrs,

Headaches that started within 3 months of a head/neck injury. Headaches must either 1) last 4 or more hours a day and reach a moderate to severe intensity at any point during the headache or 2) may be of any severity or duration if the participant takes a medication in an effort to stop the headache. Headaches meeting these criteria must have been present on average at least 8 days per 4-week period over the 3 months preceding study enrollment.

Comorbid PTSD or other anxiety disorder is not exclusionary.

Fluency in English is required.

Persons of all races and ethnicities are eligible.

Female participants must agree to abstain from sexual relations that could result in pregnancy or use a reliable form of birth control during the study.

Continued use of prophylactic migraine medication other than the study drug is permissible if the participant has been on a stable dose for at least 4 weeks prior to the preliminary screening period and intends to continue the medication for the duration of the trial.

Exclusion Criteria:

History of TBI more severe than that classified as mild by DVBIC criteria

Significant headaches preceding the onset of posttraumatic headaches. Specifically, a prospective subject may not have had moderate or severe headaches occurring more than 2 days per month average or more than 5 lifetime migraine headaches

Continuous headaches of any severity, i.e., persistent daily headaches with no headache-free period less than 8 hours between attacks

Unable to reliably keep the headache log on a minimum of 80% of recordable days

Women of childbearing potential must not be pregnant, planning to become pregnant during the study period, or nursing.

Participation in a headache support group or other activity such as meditation or yoga intended to mitigate headache or other chronic pain must be stable for at least 4 weeks prior to beginning the preliminary screening period and should be intended to be continued for the duration of the trial. Participants will be encouraged to defer enrolling in such activities until they have completed the treatment trial.

Medication Exclusions:

Current use of prazosin at a dose of >2 mg or other alpha-1 antagonist for any purpose

Use of prazosin at a dose of 2 mg or less is not excluded, however there will be a 2-week wash-out period prior to beginning the baseline headache log-keeping period.

Allergy or previous adverse reaction to prazosin or other alpha-1 antagonist

Subjects must be on a stable dose of the following medications/treatments for at least 4 weeks prior to the preliminary screening period, and must intend to continue the medication for the duration of the trial: psychoactive drugs, for example anticonvulsants, benzodiazepines, antidepressants, sedative/hypnotics; antihypertensive medications, including beta blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers; magnesium prescribed specifically for headache.

Potential participants who have been taking trazodone will undergo a 2-week washout period before beginning the preliminary screening period. Because combining prazosin and trazodone may increase risk of priapism, trazodone is not allowed during the study.

Sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra) will not be permitted during the dose titration period, because of increased risk of hypotension in combination with alpha-1 blockers, but will be allowed at half the usual starting dose following the study drug dose titration period, per VA prescribing guidelines.

Use of butalbital within 4 weeks of beginning the preliminary screening period through the end of study involvement.

Use of supplements containing nitrates and supplements containing stimulants (such as ephedra) within 2 weeks of beginning the preliminary screening period through the end of study involvement.

Use of prescribed stimulants (such as amphetamine or dextroamphetamine containing medications) within 2 weeks of beginning the preliminary screening period through the end of study involvement.